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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-03-0782.
Submitted March 13, 2002
Accepted July 1, 2002
Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency
Frank Yates, Michele Malassis-Seris, Daniel Stockholm, Cecile Bouneaud, Frederique Larousserie, Patricia Noguiez-Hellin, Olivier Danos, Donald B Kohn, Alain Fischer, Jean-Pierre de Villartay, and Marina Cavazzana-Calvo*
Cellular and Gene Therapy Department, Hopital Necker-Enfants Malades, Paris, France
CNRS URA 1923, Genethon III, Evry, France
INSERM Unite 277, Institut Pasteur, Paris, France
Laboratoire d'Anatomie Pathologique, Hopital Necker-Enfants Malades, Paris, France
Division of Research Immunology / B.M.T., Childrens Hospital, Los Angeles, CA, USA
* Corresponding author; email: cavazzan{at}necker.fr.
Patients with mutations of either RAG-1 or RAG-2 genes suffer from Severe Combined Immuno-Deficiency (SCID) characterized by the lack of T- and B-lymphocytes. The only curative treatment today consists of haematopoietic stem cell (HSC) transplantation, which is only partially successful in the absence of an HLA genoidentical donor, thus justifying research to find an alternative therapeutic approach. To this end, RAG-2-deficient mice were used to test whether retrovirally mediated ex vivo gene transfer into HSC could provide long-term correction of the immunological deficiency. Murine RAG-2-/- Sca-1+ selected bone marrow cells were transduced with a modified MND retroviral vector containing the RAG-2 cDNA, and transplanted into RAG-2-/- sublethally irradiated mice (3Gy). Two months later, T and B cell development was achieved in all mice. Diverse repertoire of T cells as well as proliferative capacity in the presence of mitogens, allogeneic cells and KLH were shown. B cell function as shown by serum Ig levels and antibody response to a challenge by KLH also developed. Lymphoid subsets and function were shown to be stable over a one-year period without evidence for any detectable toxicity. Noteworthy, a selective advantage for transduced lymphoid cells was evidenced by comparative provirus quantification in lymphoid and myeloid lineages. Altogether, this study demonstrates the efficiency of ex vivo RAG-2 gene transfer in HSC to correct the immune deficiency of RAG-2-/- mice, constituting a significant step towards clinical application.
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